Clinical Applications of Neuroscience A Journey into Understanding , Observation and Application of Metabolic Rate

Presented by the Carrick Institute for Graduate Studies Frederick Robert Carrick, DC, PhD, DACAN, DABCN, DACNB, DAAPM, FRCPN, FACCN, FAAFN, FEAC (Neurology), FACFN, FABVR, FABES, FABCDD, FICC Professor Emeritus of Neurology, Parker College Distinguished Post Graduate Professor of Clinical Neurology, Logan College Professor of Clinical Neurology, Carrick Institute

J. Brandon Brock RN, BSN, MSN, NP-C, DC, DACNB, FACFN, FABVR, FABCDD, FABNN, FABES, FICC, R.NCS.T, CNCT Professor of Neurology, Carrick Institute Family Nurse Practitioner Chiropractic Neurologist / Fellow - Electrodiagnosis, Vestibular Rehabilitation, Nutrition and Neurochemistry, Childhood Disorders.

Copyright © 2012 J. Brock / Carrick Institute, All Rights Reserved Special thank you to all of the Carrick Institute Faculty. Each of which have contributed to the growth of this course, the concepts discussed and applications that have been developed. Clinical Features of – Neurological Death

• In order to understand neurological conditions from a functional perspective, one must understand the brain and cortex and related functions. You also cannot bypass ablative neurology. – End organ and receptor – Peripheral nervous system – Spinal cord – Brainstem – Cerebellum – Basal Ganglia – Vasculature – Cortex – Physiology – Labs – Imaging

Notes Most Important Factors for Treatment

• That you know where the problems is from an anatomic point of view. To do this, you have to be able to do a physical examination and patient intake. • The next part of this is to know which receptor based systems will activate the area of pathology. • To be cross trained. Endocrinology, immunology, functional lab analysis, diagnostics and medication. The trick here is learning how to combine metabolic therapy and receptor based therapy in the right order and the right times. (Best therapists the exist at the best at this). • Be the master at controlling fuel for delivery. • Be the master at giving the right combination of treatments at the appropriate rate.

Treatment • Is there a good side and a bad side to activation? • Is there an importance to learning how to monitor for fatigue? • “The difference between good and great functional neurologists is knowing when to treat and how much treatment to give and when to stop”. • Sometimes less is more, sometimes less supplementation is better. Sometimes supplementation is all that will work in a given metabolic situation. Sometimes medications are the only option. Sometimes treatment is out of your scope.

Notes Things to Monitor

• Any objective clinical finding. • Any subjective clinical finding. • Autonomics • Sensory function • Motor function - movement • Cognition • Ocular function • Reflexogenic function

Make your list of what you commonly monitor and how you monitor it “Head Trauma” A Model of Metabolic Function • One head injury, one infection, one exposure to various chemicals can lead to immunologically based – inflammatory mediated periods of concussion that may be sustained for long periods and gain physiological efficiency. Head Trauma • Can lead to the following – Chronic encephalopathy – Neurodevelopmental disorders. – Reactive oxygen species – Reactive nitrogen species – Lipid peroxidation products – Prostaglandin production – Dendritic retraction – Myelin damage – Synaptic injury – Microtubular damage – Mitochondrial suppression. – Cell wall damage – DNA damage – Hyperphosphorylation – Microglial priming – BBB degeneration – Insulin dysregulation – Hormonal fluctuation – Autonomic dysregulation

Notes Head Trauma • Several loops / scenarios to consider – Immunological – excitotoxic loop. – Excitotoxic – microglial priming loop. – Peripheral immunological macrophagic infiltration loop. – Dual cytokine – glutamate synergism. – TNF alpha , IL1b, Quinolinic - AMPA, NMDA Kianate antagonism. – IDO – INF gamma – Kyurene – QUIN – tryptophan loop. – QUIN – excitotoxic – hyperphosphorylation loops. – Synuclein – amyloid – tau – Oligomer relationships.

Notes Immediate Clinical Considerations to Ponder! 1. Is there a component of conservativeTrauma treatment (Trauma –for immune head trauma? – excitotoxic loops) 2. Is there a metabolic link to trauma? 3. Can traumatic situations continue• Excitoto accumulate-toxicity sustained tissue damage? 4. Are there ways to make a change• inReactive this loop? O2 Species 5. Can this loop create collateral damage• Reactive – disease? nitrogen species 6. Is there a methodical way to deal• withAccumulation this story? of Lipid Peroxidation 7. Does this story have anything to• whatProstaglandin we see clinically? activity 8. How does this story related to the• Dendriticmodern day retraction neurological examination? 9. How does this story relate to the• modernSynaptic day injury subjective intake. • Mictrotubular degeneration • Mitochondrial suppression

Notes Can you name things

• Can you discuss the basic terms and concepts thus far that we are going to expand upon? Receptors and Excito-toxicity

Mg2+ NMDA AMPA receptors receptor

Ca2+ Na+

synaptic strengthening With lowhigh presynaptic presynaptic activity activity only most some of the of AMPA the AMPA receptors are activated,activated and giving the rise EPSP to ais weak strong. EPSP.

The strong EPSP (or back-propagated action potential) Underlifts the these Mg2+ circumstances block of the NMDA the NMDA receptor. receptor is inactive despite binding of glutamate because its 2+ channelThe Ca2+ is signal blocked ultimately by Mg leads . to synaptic strengthening. glutamate Ca++ Na+ Mg++

glycine

co-agonists open the channel, restingbutLong it -but termis blocked blocked potentiation by Mg++ by Mg++synaptic- not depolarized plasticity

NMDA receptors open & unblocked

Spectrum of Excitation by Glutamate at NMDA Receptors Energy linked excito-toxicity Autoimmunity to Excito-toxins NMDA receptors Genetic disruption Inflammation BBB dysfunction Glutamate Genetic

Excitotoxicity - damage to Excess excitation neurons - psychosis - mania Excitotoxicity - panic - slow neurodegeneration Normal excitation and long-term potentiation Excitotoxicity - catastrophic neurodegeneration NMDA Receptor Summary

• What helps control NMDA receptors. – Activation – Genetics – EEE / Mitochondrial function / BBB / Inflammation – Stress (Catecholamine levels). – Immune modulation. – Homocysteine levels – B vitamins – EFA’s – Heavy metal modulation – Mg – Drugs: Memantine, Amantidine, Ketamine, d-cycloserine, L calcium channel blockers.

We will discuss how the NMDA pathway ties into glutamate and other transmitters as we progress through the lecture. DISC-1 neuregulin DISC-1

Consider dysfunction Inflammation, Activation, EEE death inadequate neurogenesis poor neuronal migration

DISC-1 inadequate neuregulin synapse selection/ axonal neurite outgrowth

abnormal glia poorly abnormal innervated development myelination dendritic tree

• What therapies or interventions can you use to have a direct impact in the receptor – calcium based systems we just discussed? Link to Calcium and Magnesium Disturbances in Calcium levels

• Seen in virtually every disease in the central nervous system that is considered to be related to “neurodegeneration”. Virtually all other mechanisms that occur have this as a cornerstone to its pathophysiological model. • If the homeostatic control mechanism of calcium is disturbed, a disease process will occur. Calcium Control

Calcium levels – control and concentrations determine whether a cell will grow or degenerate 1. Action potentiation 2. Calcium receptors activated 1. Voltage gated calcium channels 2. NMDA receptors 3. ACH / glutamate receptors 3. Calcium levels rise via influx into the cytosol 4. Calcium levels rise via influx from the endoplasmic reticulum. 5. This influx must happen to create learning and memory. (ie – hippocampus) 6. LTP is divided into three temporal phases 1. STP (Short term): Activated via protein kinase and protein synthesis independent 2. E-LTP (Early long term potentiation): Activated via protein kinases and the insertion of glutamate receptors into the post synatptic membrane. 3. This will recycle the activation of the AMPAR.

Notes AMPAR ACH / Glutamate

Threonine / tyrosine A Functional Nervous System

Receptor Activation (Trk/P75NTR/RTK/NMDA Receptors) Temporal/Spatial Summation EPSP/IPSP Fuel (O2 & Glucose) Na & Ca K Pathologies Synaptogenesis

Mg Receptor health/formation

NMDA/AMPA: ATP Plasticity Glutamate receptors Mitochondria Cellular health Kinase activation LTP Apoptosis

CIEGR C-fos/jun/mar Kinases: NT Production transfer phosphates from ATP (phosphorylation) Microglial cells and Up-regulates cytokines 2nd order neuron An Excitotoxic Nervous System Receptor Activation Inflammation Temporal/Spatial Summation Excessive Glutamate/Aspartate: EPSP/IPSP brain injury, inflammation, exogenous intake, X mitochondrial damage, etc. Fuel (O2 & Glucose) Na & CaCa K X Synaptogenesis

Mg Receptor health/formation Plasticity NMDA/AMPA: ATPX X Glutamate receptors MitochondriaX Activates: Cellular health Kinase-Proteases activation damage cell proteins X -Phospholipases damage lipids LTP -Endonucleases damage DNA X -iNOS & Super Oxide Anion -PerioxynitrateCIEGR C-fos/jun/mar NT Production

Up-regulates 2nd order neuron Notes There are many forces at work in in the nervous system: AMPA – Kainate – NMDA – Glutamate – Plastic responses Calcium Induced Excito-toxicity • Apoptotic Pathway – Intracellular calcium dysregulation – Induces DNA degredation via endonucleases – Induces phospholipase activation – Induces protein degredation via calpain – Induces mitochondrial failure. (Inhibits Krebs) – Induces lipid peroxidation via nitration via calcium – calmodulin and NOS. • NO reacts with superoxide anions producing perioxy nitrite which is a free radical which activates lipid peroxidation which activates polyADP-ribose polymerases which activates proapoptotic NF-KB p53 Notes

Notes Calcium Induced Excitotoxicity

• Mitochondrial failure leads to Energy linked Perpetuation. – ADP – P / without ATP production due to ETC failure. – Phosphorylation of bi-lipid membranes. Membrane fragility. – Excess Phosphate which opens NMDA channel. Excess calcium influx (Dysregulation) – NA / K ATP dependant pumps fail. (Osmotic changes) – Intracellular NA accumulates (Cell becomes more positive inside) – Neuron Changes threshold (TND – Frequency of firing) – Neuron swells (May rupture or metabolically fail) – CIS changes. Notes Ca+ Ca+ cytokines Ca+ polyamine Glycine & Glutamine Na Mg P BDNF, GF, Ca+ P75 Ca+ kinase Ca+ er Kainate

Nucleus

P

Trail Proteins transcribed P Weakened cell membrane P P Mitochondria Careful of additives that ALWAYS have MSG • Some spices • Hydrolyzed protein • Carageenan • Hydrolyzed plant protein • Soy protein concentrate • Plant protein extract • Soy protein isolate • Sodium caseinate • Why protein concentrate • Yeast extract • Careful with shellfish • Textured protein • Autolyzed yeast • Hydrolyzed vegetable • Hydrolyzed oat flour protein actually has • Malt extract aspatate, glutamate and cysteic acid and some • Malt flavoring carcinogens. A very • Bouillon dangerous combination • Broth • It you eat out, eat it out of a • Stock can, eat it out of a box or • Natural beef or chicken have preservatives – get flavoring ready, you have been exposed.

YouTube: Electron Transport Chain Animation Overview (Chemiosmosis)

Oxygen

ETC: Electron Transport Chain Complex I-IV Oxidative are proteins. Complex V Phosphorylation: is ATP-synthase. donate electrons to eventually form ATP e- donor Metabolism Creates Reactive Oxygen Species (ROS) which promote Oxidative Stress X

Oxidative Stress uncouples Complex I & II & X damages mitochondrial DNA When some H+ leaks prematurely to oxygen, the y produce the Superoxide Free Radical.

e-acceptor: o2 which is reduced to H2O Notes Time to Review

• What is plasticity? • What is excitotoxicity? • Why do you need to even care as a chiropractor? Apoptotic Pathway Two • Caspase Cascade – Death receptors (Fas / TNFR / p75 / TRAIL)?? – Intracellular caspases are activated and lead to lipid peroxidation. Same common pathway as perioxynitirite. – Activates apotosis via activation of NF-KB. – Abnormal – Proinflammatory cytokines will activate straight into this pathway that ultimately activates NF-KA and ultimately leads to cellular death. Making the leap • Taking the jump from excitotoxicity to reactive species. Reactive species create cell damage. Reactive Oxygen Species Reactive Nitrogen Species Lipid Peroxidation

Notes

Notes

Immune system – glial cells and cytokines. What business do they have in the story DHA

Int. J Neurosci. 1996 Nove;87(3-4):141-9. Essential fatty acids preparation (SR-3) improves Alzheimer’s patient’s quality of life. Notes

Notes

Ca+ Low O2 Ca+ cytokines Low Sick Cell Ca+ glucose polyamine Glycine & Glutamine Na AlphaMg Lipoic Acid Ca+ P Ca+ BDNF, GF, Ca+ P75 Ca+ kinase Ca+ er Na K Ca+ Na Kainate Glu Nucleus AlphaSOP Ketoglutaric PON Acid histones Huperzine VinpocetineNOS P

Trail Proteins transcribed DHAP Weakened cell membrane Lipid perox P N F K B P Acetyl – L - MitochondriaGlutathioneAdenosine Carnitine Coryceps augments Glutathione Apigenin Alpha Lipoic acid and Gotu Kola Curcuminbaicaleincytokines Selenium augments Milk Thistle Luteolin Glutathione Augment Glutahtione Summary as it pertains to TND ↓Fuel/Activation & ↑Inflammation Promote…

• Transneural Degeneration (TND) – Decrease oxidative phosphorylation in mitochondria – Decrease ATP so decrease energy to all points of cell (nucleus decreases cIEG, ribosomes can’t create protein for repair, etc.) – Na/K pumps fail, shift t/w Na equilibrium (innate survival mechanism to continue to perform its function) – Cellular swelling (Na hydrophilic) – Nucleus eccentric (decrease tubulin) – Anaerobic metabolism and lactic acid – More acid = lower pH – Retrograde chromatolysis (dissolution of Nissl) – Cell cannot repair itself, cannot create NT, receptors, etc. – Ca influx activates neutral proteases and phospholipases which liberates arachidonic acid, inflammation, and free radicals. • Kyurenic – Quinolinic – IDO – tryptophan inormation.

Notes Head Trauma • Several loops / scenarios to consider – Immunological – excitotoxic loop. – Excitotoxic – microglial priming loop. – Peripheral immunological macrophagic infiltration loop. – Dual cytokine – glutamate synergism. – TNF alpha , IL1b, Quinolinic - AMPA, NMDA Kianate antagonism. – IDO – INF gamma – Kyurene – QUIN – tryptophan loop. – QUIN – excitotoxic – hyperphosphorylation loops. – Synuclein – amyloid – tau – Oligomer relationships.

Notes Degenerative Disorders

• Alzheimer’s (Amyloid / tau pathology) • Dementia with Lewy bodies (Alpha-synuclein pathology) • Parkinson dementia (Alpha-synuclein pathology • Protein folding • CHT and pugialism concussion • Multi-system atrophy (Alpha-synuclein pathology • Fontotemporal Dementia (Tau pathology) • Progressive supranuclear palsy (Tau Pathology) • Corticobasilar degeneration (Tau Pathology) • Huntingtons Disease (Trinucleotide repeat) • Spinocerebellar ataxia (Trinucleotide repeat) • Wilsons Disease (Copper) • Hallervorden-Spatz (Iron) • Metachromatic Leukodystrophy (Leukodystrophy) • Prion related diseases

Practicum

• Please describe all of the last portion of the how the aforementioned diseases occur and what their physiological problems are and how you recognize and monitor them. Can Treatment Prevent or Reverse the Damage?

STRESS1 Dendritic 2 ?? branching Increased survival Glucocorticoids Atrophy/death and growth of neurons BDNF

BDNF

Normal survival Glucocorticoids and growth 5-HT and NE

Pharmacotherapy, ECT, psychotherapy1

5-HT=serotonin; NE=norepinephrine; ECT=electroconvulsive therapy.

1. Duman RS, et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48(8):732-739. 2. Sapolsky RM. Glucocorticoids and Hippocampal Atrophy in Neuropsychiatric Disorders Arch Gen Psychiatry. 2000;57(10):925-935. Methylation Pathway Cycles My Waiting Room 1 Urea Cycle 2 Neurotransmitter (BH4) cycle 3 Folate cycle 4 Methionine 4 Methionine (methylation) cycle 3 THF SAMe 5 Transulfuration cycle Cancer Mutatioins anywhere in this pathway can Thymidine compromise critical functions in the body synthesis methylation DNA, RNA 2 Protein, lipds dUMP 1 Tryptophan Tyrosine MTRR DMG Guanido Ac MTR Arginine BHMT BH4 TMG Creatine Creatinine SAH MTHFR Ornithine DHPR adenosine

NOS SAHH Homocysteine Urea Ammonia Vascular 5 Methyl CBS 5 BH2 THF

Cystathionine B6, P5P 2 BH4 2 Dopamine Mood Serotonin Ammonia Brain MAO A MAO B Cystine + α KG Fog

NorEp Citrulline + NO 1 BH4 1 HIAA COMT MAO B Taurine Sulfite Glutathione Neuronal Peroxynitrate COMT Damage

HVA moly SUOX 0 BH4 0 VMA Sulfate Microglia Superoxide Activation Neuropathy/Inflammation METHYLATION MAP Oxidative-Inflammatory Disease

Datis Kharrazian Optimal Function

Fuel for delivery and related factors • Glucose (Nutrients). – Example: Diabetes / malabsorption, etc. • Oxygen (O2 and carrier components). – Example: Anemias, COPD, etc. • Activation. – Example: Disuse, injury, myopathy, peripheral nerve damage, subluxation, etc. • Transmitter levels / Neurochemical environment. – Example: TND – changing dopamine, serotonin, ACH, etc. • An environment that is “synaptic friendly.” – Example: Inflamed, infected, avascular, etc. • Genetic “epigenetic” factors. – Example: Heredity, triggered mutations, etc. Notes Kharrazian

89 Kharrazian

90 Kharrazian 91 Kharrazian 92 Kharrazian

93 Kharrazian 94 Basic Pathway Principles Pathways

• We must review some basic pathways before we progress though each transmitter. • As we discuss each transmitter, the information about each pathway will increase. • If you cant work through these, you are going to have difficulty with drugs and supplements to help your patients. Anatomy

corpus callosum cingulate gyrus DLPFC

caudate nucleus accumbens thalamus VTA raphe hypothalamus

LC amygdala

hippocampus striatum thalamus prefrontal hypothalamus cortex PFC cerebellum S T NA BF Hy C brainstem basal A NT neurotransmitter forebrain H centers nucleus accumbens amygdala SC spinal cord hippocampus Some Key Behaviors Hypothetically Linked to Specific Brain Regions delusions hallucinations pleasure interests motor libido critical relay site from PFC fatigue pain euphoria sensory relay to and from cortex reward alertness executive function motivation attention concentration emotions impulses PFC obsessions compulsions S motor T NA fatigue BF ruminations Hy worry C pain negative symptoms A NT motor guilt H suicidality memory alertness pain fear SC anxiety memory sleep panic reexperiencing appetite endocrine Match Each Symptom Associated with Mania to Hypothetically Malfunctioning Brain Circuits

delusions overactivity hallucinations aggression hypersexuality substance abuse overactivity

PFC S T NA BF impulsivity Hy substance abuse NT aggression A hypersexuality H SC

anxiety Dopamine Projections from Neurotransmitter Centers

PFC S T NA BF

Hy A NT H

SC Norepinephrine Projections from Neurotransmitter Centers

PFC S T NA BF

Hy A NT H

SC Serotonin Projections from Neurotransmitter Centers

PFC S T NA BF

Hy A NT H

SC Acetylcholine Projections from Neurotransmitter Centers

PFC S T NA BF

Hy A NT H

SC Acetylcholine Projections from the Basal Forebrain

PFC S T NA BF

Hy A NT H

SC Histamine Projections from the Hypothalamus

PFC S T NA BF

Hy A NT H

SC The histamine center is in the hypothalamus (TMN, tuberomammillary nucleus), which provides input to most brain regions and the spinal cord. Cortico-Cortical Interactions

PFC area PFC area 1 2

Association fibers and inter-hemispheristic connections Neurotransmitter Nodes Influence Prefrontal Cortical Nodes and Their Cortico-Cortical Interactions

PFC area PFC area 1 2

neuro- transmitter nodes Some Important Circuits and Connections Involving the Prefrontal Cortex

DLPFC

OFC Prefrontal Circuits Striatal loops A Direct and Indirect loops H Cortico-Striatal-Thalamic-Cortical (CSTC) Loop

prefrontal cortex A must know circuit -Behavior -movement striatal -cognition complex Major player with therapy

thalamus Neurotransmitter Nodes Influence CSTC Loops and Their Interactions

prefrontal cortex

striatal complex

thalamus

neuro- transmitter nodes Cerebral cortex Thalamus G GA G G Ga GA Caudate / Putamen / NA Ret. N D2 Striatum D1 Da Ga Ga/SP GPi/SNr G SNc Ga GPE GA STN G

G G Mes M. Ga PPN Colliculus Brainstem / SC G H and V gaze centers Hypothetical CSTC Loop for Executive Functions DLPFC Striatum Thalamus DLPFC Hypothetical CSTC Loop for Attention Dorsal ACC Bottom of Striatum Thalamus ACC Hypothetical CSTC Loop for “Emotions”

Subgenual ACC Nucleus Accu Thalamus Cortex Limbic Loop

Cortex Anterior cingulate gyrus Temporal cortex Entorhinal cortex Hippocampus Thalamus Inferior Prefrontal cortex MD parvo

Ventral Striatum GPI Nucleus Accumbens Ventral palladium

Hippocampus Amygdala

Ventral Tegmentum

GPE STN SNPC Hypothetical CSTC Loop for Impulsivity/Compulsivity

OFC Bottom of Caudate Thalamus OFC Cortex

Striatum Nucleus Accumbens GPI Thalamus

DA

DA PC PR

NE Ventral 5htp Tegmentum

Cocaine binds dopamine reuptake in VTN Amphetamines are dopamine releasing agents RN LC Nicotine excites plasma excitatory receptors Opiates increase mesolimic and mesocortical projections Hypothetical CSTC Loop for Motor Activity Prefrontal Putamen (Lateral Striatum) Thalamus Cortex Motor Cortex

The motor loop Primary motor cortex Premotor / Supplementary Motor Primary Sensory cortex Thalamus VA MD VL

Striatum / Putamen D2 D1

GPI Internal segment Lateral and medial SNPr

SN GPE PC STN Layers of the Cortex

• The actual functional part of the cortex involves a thin layer of neurons 2 to 5 mm thick which covers all of the convolutions of the cortex. • The surface area of the cortex is about one square meter and contains around one billion neurons. • There are essentially six layers of the cortex, with the sixth layer essentially being divided into two layers. • Most of the cells in these layers are of three different varieties, granular (also called stellate), fusiform and pyramidal. • The granular cells in general have short axons and therefore serve as intracortical interneurons. Some are excitatory (Glutamate) and some are inhibitory (GABA) in nature. • The sensory areas and the association areas of the cortex have large concentrations of these types of neurons due to a significant amount of intracortical processing of incoming sensory signals and cognitive analytical signals in the association areas. • The pyramidal and fusiform cells give rise to the output fibers of the cortex. The pyramidal cells are the most numerous and the largest and comprise the pyramidal pathways and the large association fibers pass from one major part of the brain to another.

Function of Cortical Layers

• The most outer layer is the molecular layer and is considered to be layer number one. • The second layer, or one layer lower from the surface is the external granular layer. • The third layer is the layer of pyramidal cells and the next layer or the fourth layer is the internal granular cells. • The next which is the fifth is the large pyramidal cell layer. The last which is the sixth is the layer of fusiform or polymorphic cells.

There is some understanding of basic functions of these layers.

• Incoming sensory signals are what drives our neuraxis and these synapse onto layer 4 (Internal granular layer) for excitation and the signal spreads rostral and caudal. • At the same time layers one and two (Molecular and external granular) are receiving diffuse, nonspecific input from lower brain centers that can facilitate a specific region to give a resultant desired response of that region. • These areas basically create a certain level of regional excitation.

Layer functions cont.

• The neurons in layers two and three (External granular and pyramidal) send axons to other areas or portions of the cortex, including those fibers that traverse through the corpus callosum. • Now neurons in layers 5 and 6 (large pyramidal layer and fusiform and polymorphic) send projections to the more distant and deeper areas of the nervous system. For example, those in layer five (large pyramidal cell layer) send projections to the basal ganglia, brainstem and spinal cord for control signals in these areas. The sixth layer (fusiform and polymorphic) cells send projection to the thalamus for feedback signals from the cerebral cortex to the thalamus.

Output from Cortical Pyramidal Neurons

lamina

1

2

3

4

5

6 white matter

glu glu glu glu glu other striatum brainstem thalamus cortical areas Interneuron Input to Cortical Pyramidal Neurons

GABA

GABA GABA

GABA

GABA GABA

glu Input to Cortical Pyramidal Neurons

glu glu glu glu glu glu glu glu glu glu glu

glu

ACh HA

other brainstem other cortical monoamine neuro- areas transmitter thalamus centers centers

glu Two Molecular Sites Critical for the Efficiency of Cortical Circuits

monoamine degradation (e.g. COMT, monoamine MAO-A) transporter (e.g. SERT) Matching the Symptom to a Hypothetically Malfunctioning Circuit problems concentrating

A

anxiety

overactivation normal baseline hypoactivation Considering the Key Neurotransmitters Regulating the Hypothetically Malfunctioning Circuit

problems concentrating

DA DA HA neuron

HA 5HT neuron neuron

TMN GABA neuron

NT center NT center

anxiety overactivation normal 5HT GABA baseline hypoactivation Selecting or Combining Treatments that Act Upon Key Neurotransmitters Regulating Hypothetically Malfunctioning Circuits

norepinephrine dopamine reuptake Diet – Activation – Nutrition can affect all areas. problems inhibitor (e.g., bupropion) concentrating

DA HA

stimulant / modafinil anxiety

5HT SSRI GABA benzodiazepine SNRI cognitive behavioral therapy Affect of Fear

overactivation normal baseline hypoactivation

ACC

OFC amygdala

fear Avoidance

overactivation normal baseline hypoactivation

PAG

fear response amygdala motor responses periaqueductal gray fight/flight or freeze Endocrine Output of Fear

overactivation normal baseline hypoactivation

hypothalamus

fear response amygdala endocrine hypothalamus cortisol coronary artery disease type 2 diabetes stroke

Breathing Output

overactivation normal baseline hypoactivation

PBN

fear response amygdala respiratory parabrachial nucleus respiratory rate shortness of breath asthma

Autonomic Output of Fear

overactivation normal baseline hypoactivation

LC fear response amygdala cardiovascular locus coeruleus atherosclerosis cardiac ischemia BP HR variability MI sudden death Reexperiencing

amygdala hippocampus Selecting or Combining Treatments that Act Upon Key Neurotransmitters Regulating Hypothetically Malfunctioning Circuits

norepinephrine dopamine reuptake Diet – Activation – Nutrition can affect all areas. problems inhibitor (e.g., bupropion) concentrating

DA HA

stimulant / modafinil anxiety

5HT SSRI GABA benzodiazepine SNRI cognitive behavioral therapy Potential Therapeutic Effects of GABA-ergic Agents

areas of overactivation areas of normalized activation

PAG hypothalamus ACC

OFC LC

PBN amygdala GABA neuron Potential Therapeutic Effects of GABA-ergic Agents

areas of overactivation areas of normalized activation

amygdala GABA neuron Potential Therapeutic Effects of GABA-ergic Agents

areas of overactivation areas of normalized activation

amygdala GABA neuron fear Potential Therapeutic Effects of GABA-ergic Agents

areas of overactivation areas of normalized activation

GABA amygdala action GABA neuron fear Potential Therapeutic Effects of GABA-ergic Agents

areas of overactivation areas of normalized activation

GABA action GABA neuron fear Potential Therapeutic Effects of Alpha 2 Delta Ligands

areas of overactivation areas of normalized activation

PAG hypothalamus ACC

OFC LC

PBN amygdala

fear = 2 ligand Potential Therapeutic Effects of Serotonergic Agents

areas of overactivation areas of normalized activation

5HT neuron

raphe

amygdala

5HT action fear Potential Therapeutic Effects of Serotonergic Agents

areas of overactivation areas of normalized activation

PAG hypothalamus 5HT neuron ACC raphe

OFC LC

PBN amygdala

14-27 Promoting GABA & Glutamate Balance

Taurine 1000 mg Acts as an endogenous GABA agonist Rescues neurons from excito-toxic effects induced by elevated glutamate

Blocks NMDA voltage gated receptors reducing Magnesium (malate) excitatory post synaptic receptors 200 mg Reduces neuromuscular irritability, seizures, etc. Cofactor in synthesis of gaba from the enzyme glutamic B6 25 mg acid decarboxylase (GAD)

Green tea extract 300 Attenuates glutamate cytotoxicity Activates PI3/AKT and inhibits GSK3, an effect similar to mg (Camilla sinensis) – 60% lithium catechins, 40% EGCG N-acetylcysteine (NAC) Natural NMDA receptor antagonist 600 mg Protect nerve cells from harmful excitotoxic effects Precursor to glutathione, a primary antioxidant in the body as well as in the central nervous system 147

Nutient Support for GABA Glutamate Balance

Vitamin B6 25 mg (as pyridoxine HCl) G.A.D. - GABA support

Magnesium 200 mg (as magnesium malate)

Taurine 1,000 mg

N-Acetylcysteine 600 mg

Green Tea Leaf Extract 300 mg, Decaffeinated Additional GABA producing products

• Valerian root – Affinity for GABA receptors. Also shuts down sympathetics. • Lithium Orotate – Increases GABA activity. • Passion Flower Extract – Acts on GABA receptor system. • L-Theanine – Crosses BBB – dampens excitotoxicity, increases GABA • Taurine – Similar in structure as GABA

FFitzgerald / Curran FNetter Tryptophan (Dietary from periphery)

Protein carrier (large neurtral aminoa acid transporter) BBB

Tryptophan Iron / Folate / B3 / Calcium Serotonin (5-Hydroxytryptamine) Tryptophan Hydroxylase TPH-1 / TPH-2 Pyridoxal – 5 - Phosphate O2 / Tetrahydrobiopterin Niacinamide Methylcobalamin 5-Hydroxytryptophan L –amino acid decarboxylase Folic Acid Magnesium / Zinc / Vitamin C BCAA ratios and Insulin

• Tryptophan is in competition with several other amino acids. – Leucine / isoleucine and valine – There is a delicate balance between the aforementioned and tryptophan. – This depends on insulin surges in the body.

Insulin sensitization / Surges

Elevated Insulin rapidly absorbs leucine, isoleucine and valine Impacts other transmitters

Elevated Cortisol Tryptophan is left in the system at an elevated ratio Inflammation Glycosolated End products

Elevated Insulin and Tryptophan create elevated serotonin Coaguloapthies

Fluid retention and blood pressure changes Fatigue / Drowsiness In creases Triglycerides Cholesterol dysregulation Insulin and dysglycemia Hormone Imbalance Genetic variations GI malabsorption Under Activation Gastric Dysfunction Emotional Distress Anemia TND / Excito-toxicity Adrenal Dysfunction

Serotonin

1. Eliminate stress 1. Diet 2. Eliminate Dysglycemia 2. Lifestyle 3. Eliminate absorption or digestive issues 3. Activation 4. Eliminate hormonal fluctuation 4. Supplementation 5. Eliminate sedentary lifestyle 5. Drugs 6. Eliminate Other factors that alter Serotonin

Supplements for Serotonin

• 5-HTP (Precursor support) • St. Johns Wort (Natural MAOI) • SAM-e (Methyl donors) (Methylation and sulfation) – Tyrosine and H-HTP supplements need methyl donors and using these products will deplete sulfur amino acids. SAM- e alleviates both issues. If you can’t use SAM-e, cysteine works well. • Cofactors (Niacin, B6, B12, magnesium, calcium. zinc). • L-Tryptophan (Precursor support) • Estrogens (Isoflavones) Serotonin Support

Precursor loading 5 HTP or Tryptophan Stimulation of TH Iron, Methyl-Folic-Acid (BH4), B6, (tryptophan hydroxylase) sulfur donors Inhibit serotonin reuptake DHEA – also prevents Quinolinic Acid (Glutamate) Stimulate serotonin release Meditation, Yoga, Massage, Nuturing, receptor based stimulation Support post synaptic receptor DHA, Vitamin D - 5HT1A

Inhibit degradation Natural MAO Inhibitors (St. (MAO inhibitors) Johns Wort extract) Functional Neurological Treatment

• Frontal Stimulation – Exercise , motivation, positive thinking, biofeedback • Amygdalar limbic stimulation – Nurturing, love, appropriate ventral tegmental activation. • Reducing stress – Meditation, relaxation, counseling, mentoring • Midline brain stem stimulation – Core exercises, VRT therapy, cerebellar therapy Medications for serotonin

• SSRIs (Selective serotonin reuptake inhibitors) • SNRIs (Serotonin–norepinephrine reuptake inhibitor ) • NDRIs (Norepinephrine-dopamine reuptake inhibitors) • NRIs (Norepinephrine reuptake inhibitors) • SNDIs (Serotonin and norepinephrine disinhibitors) • SARIs (Serotonin antagonist/reuptake inhibitors) • Tricyclics • MAOI’s (Monoamine oxidase inhibitors) Insulin symptoms

Consider the following when looking at a patient with possible serotonin fluctuations. • Fatigued after meals • Sugar and sweets cravings after meals • Need stimulants such as coffee after meals • Difficulty losing weight • Abnormal waist girth to hip girth • Frequent urination • A change in thirst or appetite (increased) • Possible weight gain when under stress • Difficulty falling asleep?

• Remember – sugar and sugar alone is responsible for insulin sensitizing.

Combining thoughts

• Do I have fluctuating signs of depression that go along with insulin surges. • Are the clear signs of insulin dysregulation along with clear signs of serotonin dysregulation. • If there is, guess what, the answer is not medication, the answer is insulin regulation. Oral precursor supplementation does not work well either until dysglycemia is managed. • Don’t forget – if you surge serotonin enough due to insulin surges or mental anguish, the levels will eventually decline. Picture the gas running out of the tank. Hypoglycemia

• This leads to a decrease in tryptophan BBB transportation. • This ultimately leads to a decrease in serotonin levels. Can also lead to pain and headaches. • Hypoglycemics also have very low levels of energy and low levels of blood sugar for brain function. The end result is bad brain function, mental fog, loss in consciousness behavioral fluctuations.

Hypoglycemic symptoms

• Irritable, shaky, or lightheaded between meals. • May feel energized after eating verses fatigued with insulin surging. • May have an energy level drop in the afternoon. • May crave sugar and sweets in the afternoon. • May wake up in the middle of the night. • May difficulty concentrating before eating. • May depend on coffee to keep going. • May feel agitated, easily upset, and nervous between meals?

Dysglycemia

• Typical order of progression. – Reactive hypoglycemia due to insulin sensitization. • Low glucose levels. May really drop after meals or before meals. – Eventual insulin resistance. • May cause insulin levels to climb even more. – Eventual Diabetes. • Glucose cannot get into all cells other than endothelial and neuronal cells. Intracellular inositol may drop, myelin may die, osmotic pressure changes occur. Activates various Sympathetic Receptors and is response Related to Dopamine various Amino Acid Dopamine Decarboxylase AAD Pathways. B6 Dopamine DOPA

Tyrosine Hydroxylase (RL) LNAA O2, iron, THB Tyrosine Tyrosine

Phenylalanine Hydroxylase Insulin Methionine, Valine, Leucine, isoleucine Phenylalanine Mesolimbic Pathway –Untreated Schizophrenia

HIGH

positive symptoms

overactivation = pure D2 antagonist normal baseline hypoactivation Mesolimbic Pathway - D2 Antagonist

HIGHLOW

reducedpositive symptomspositive symptoms overactivation = pure D2 antagonist normal baseline hypoactivation Reducing DA Hyperactivity with Lithium and Atypical Antipsychotics overactivation normal baseline hypoactivation

DA hyperactivity = lithium mania = SDA Reducing DA Hyperactivity with Lithium and Atypical Antipsychotics overactivation normal baseline hypoactivation

lithium and/or atypical = lithium mania antipsychotic = SDA reduces DA hyperactivity Mesocortical Pathway to DLPFC – D2 Antagonist

LOW

production of no improvement or secondary worsening of negative cognitive symptoms symptoms

Mesocortical Pathway to VMPFC – D2 Antagonist

LOW

production of no improvement or secondary worsening of negative affective symptoms symptoms Nigrostriatal Pathway –Untreated Schizophrenia

NORMAL

overactivation = pure D2 antagonist normal baseline hypoactivation Nigrostriatal Pathway - D2 Antagonist

NORMALLOW

overactivation = pure D2 antagonist normal EPS baseline hypoactivation blockade of D2 receptors in the nigrostriatalthis upregulation dopamine may pathway lead to causes tardivethem to dyskinesia upregulate

tardive dyskinesia Tuberoinfundibular Pathway – Untreated Schizophrenia NORMAL

overactivation = pure D2 antagonist normal baseline hypoactivation Tuberoinfundibular Pathway - D2 Antagonist NORMALLOW

prolactin levels rise overactivation = pure D2 antagonist normal baseline hypoactivation Cortical Arousal

T

HA BF Hy ACh NE

alpha 1 receptors M1 receptors H1 receptors reward: DA mesolimbic pathway

NA

VTA Neurotransmitter Regulation of Mesolimbic Reward nucleus accumbens (NA) cannabinoid

GABA PFC amygdala DA hippocampus

raphe PPD/LDT

arcuate nucleus

VTA

cannabinoid glu ACh

ACh

cannabinoid cannabinoid The Reactive Reward System

-emotional response -impulsivity NA -automatic/obligatory

GABA amygdala DA DA DA reward -“bursting” reward DA -fun learning DA -potentiation of conditioned reward

VTA glu glu

relevance detection The Reflective Reward System emotions PFC

OFC DLPFC impulses VMPFC

analysis

NA

glu glu glu glu glu GABA

final decision- integrating emotions/affect/analysis/impulses/cognitive flexibility Turning Reward into Goal-Directed Behavior

PFC

glu glu

- learning - drug seeking - long-term rewards 3 4 - short-term ventral pallidum rewards NA

1 GABA

2

GABA

thalamus Conditioning to Reward Cues

PFC overactivation normal baseline hypoactivation

NA reward amygdala learning GABA

DA DA

2 wow! 3

1 drug VTA Compulsive Use / Addiction

PFC overactivation normal baseline hypoactivation drug-seeking behavior

NA 4 amygdala drug-induced craving 1

3 reward 2 sensitivity impulsive choice

VTA Temptation 4 5 PFC cognitive drug-induced flexibility craving OFC VMPFC DLPFC

overactivation NA normal amygdala baseline hypoactivation anticipation of drug 1

3 reward 2 sensitivity impulsive choice

VTA Will Power

PFC

OFC VMPFC DLPFC

1 1 1

1 overactivation NA normal amygdala baseline hypoactivation

2

designated driver

VTA Actions of Nicotine on Reward Circuits nucleus accumbens (NA)

VTA ACh

ACh

nicotine Detail of Nicotine Actions

PFC PPT/LDT glu ACh neuron neuron

VTA nicotine indirectly activates 7 DA release 4ß2 nicotine nicotine glu directly desensitizes GABA activates ACh DA release VTA DA DA neuron GABA inter- neuron PA

ACh nicotine NPA Molecular Actions of a Nicotinic Partial Agonist (NPA)

nicotinic full agonist: nicotinic partial agonist (NPA): nicotinic antagonist: channel frequently open stabilizes channel in less stabilizes channel in closed frequently open state, state, not desensitized not desensitized Varenicline Actions on Reward Circuits

PFC PPT/LDT glu ACh neuron neuron

VTA

7

4ß2 varenicline glu varenicline GABA ACh VTA DA DA neuron GABA inter- neuron Acetylcholine and DA Release

short pulse of DA release

short burst of action potentials

ACh neuron

= ACh = Ca++ VTA DA neuron 4ß2 = DA

AChE Nicotine and DA Release

prolonged (supraphysiological) DA release

prolonged burst of action potentials

ACh neuron

= nicotine = Ca++ VTA DA neuron = DA prolonged opening of 4ß2 channel NPA and DA Release

sustained, small increase in DA release

sustained, small increase in frequency of action potentials

ACh neuron

= NPA = Ca++ VTA DA neuron = DA sustained small increase in frequency of 4ß2 channel opening Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood. Behav Pharmacol. 2008 Sep;19(5-6):641- 9. PMID: 18690118 below “simultaneous changes in dopamine (Increased) and serotonin (Decreased) “acute anorexia of nicotine infusion and acute hyperphagia of nicotine cessation.” Nutrition , Volume 16, Issue 10, Pages 843 - 857 M abstract below Smoke Virginia Slims http://www.quitsmokingpro.com/2006_09_01_archive.html All drugs have a greater impact on the developing brain “Adolescent neurobehavioral development may be altered by nicotine self-administration in a way that persistently potentiates addiction.” Neurotoxicol Teratol. 2007; 29(4): 458– 465. below Mechanism of Action of Bupropion in Smoking Cessation

ACh neuron

DA neuron

= ACh = nicotine = DA Mechanism of Action of Bupropion in Smoking Cessation

Where’s my dopamine?

= ACh = nicotine = DA Mechanism of Action of Bupropion in Smoking Cessation

Where’s my dopamine? NDRI

= ACh = nicotine = DA Actions of Alcohol on Reward Circuits nucleus accumbens (NA)

alcohol

VTA

glu

alcohol Detail of Alcohol Actions in the VTA

PFC arcuate glu nucleus neuron opiate opiate neuron receptor MGlu receptor NMDA receptor GABA-B VTA receptor alcohol GABA-A receptor glu alcohol VSCC GABA enkephalin VTA DA neuron GABA DA inter- neuron

alcohol Actions of Naltrexone in the VTA: Reducing the Reward Associated with Drinking

PFC arcuate glu nucleus neuron opiate opiate neuron receptor MGlu receptor NMDA receptor GABA-B VTA receptor naltrexone GABA-A receptor glu naltrexone VSCC GABA enkephalin VTA DA neuron GABA DA inter- neuron Actions of Acamprosate in the VTA: Reducing Excessive Glutamate Release to Relieve Withdrawal

PFC arcuate glu nucleus neuron opiate opiate neuron receptor MGlu receptor NMDA receptor GABA-B VTA receptor GABA-A receptor glu VSCC GABA enkephalin VTA acamprosate DA neuron GABA DA inter- neuron Actions of Opiates on Reward Circuits nucleus accumbens (NA)

opiates

VTA Choose your addictions wisely! Rakowski

© Rakowski 2009 Actions of Stimulants on Reward Circuits nucleus accumbens (NA)

DA

stimulants

VTA Cocaine

DA

5HT NE

caine Amphetamine Methamphetamine

DA d 94 percent of rats who were allowed to choose mutually-exclusively between sugar water and cocaine, chose sugar. Even rats who were addicted to cocaine quickly switched their “Our findings clearly preference to sugar, demonstrate that intense sweetness can surpass cocaine reward, even in drug-sensitized and - addicted individuals.” http://www.plosone.org/article/fetchArticl e.action?articleURI=info%3Adoi%2F10.1 371%2Fjournal.pone.0000698 below

© Rakowski 2008 Progression of Stimulant Abuse

amphetamine

cocaine cocaine amphetamine amphetamine

cocaine

A fun B craving C reverse D E compulsive use F “Where’s tolerance/ anhedonia marathon sex enduring paranoia my dopamine?” addicted sleepiness cognitive loss HIV “brain- violence “burn-out” withdrawal

washed” DA firing DA

time Dopamine & Addiction “They found the prevalence of the disorder in this sample to be 33% and hypothesize that attention deficit disorder in childhood (and adulthood) may be associated with an increased risk for the development of alcoholism.” http://www.ajp.psychiatryonline.org/cgi/conte nt/abstract/140/1/95 below Exercise is my “As an alternative to DRUG! drugs, the researchers point out a natural, safe, and inexpensive method of increasing dopamine levels in the brain—exercise.” http://www.pnl.gov/energyscience/03- 01/brf.htm ARTICLE BELOW I sniff amphetamines http://www.nih.gov/news/pr/nov2007/nimh-12.htm/ below

Lighter areas are thinner, darker areas thicker.

“the (ADHD) brain matures in a normal pattern but is delayed three years in some regions, on average, compared to youth without the disorder” These positron emission tomography (PET) scans show that patients with ADHD had lower levels of dopamine transporters in the nucleus accumbens, a part of the brain's reward center, than control subjects. (Image courtesy of DOE/Brookhaven National Laboratory)

http://www.sciencedaily.com/releases/2006/11/061129151028.htm© Rakowski 2009 below “All stimulants work by “Amphetamines rank fourth among 12th graders for past-year increasing illicit drug use.” dopamine levels in the brain. Dopamine is a brain chemical (or neurotransmitter) associated with pleasure, movement, and attention.” http://www.nida.nih.gov/info facts/ADHD.html below

© Rakowski 2008

“Roughly seven percent of all college students, and up to 20 percent of scientists, have already used Ritalin or Adderall.” Nature. 2008 Dec 11;456(7223):702-5. PMID: "Mentally competent adults 19060880 Towards responsible use of cognitive- should be able to engage in enhancing drugs by the healthy. http://blog.wired.com/wiredscience/mental_ cognitive enhancement using health/index.html below drugs." “The prolonged use of amphetamines (speed) or steroids can produce a loss of reality and sudden paranoia.” Joseph M. Carver, Ph.D.http://www.enotalone.com/article/4114.html below

Rapid increases in Dopamine can produce Paranoia “stress increased Fos protein expression in a distinct subset of DA neurons projecting to the prefrontal cortex.” (FOCUS AND CONCENTRATION) “In contrast, Fos expression was not increased in any DA neurons projecting to the nucleus accumbens.” (JOY) Cereb Cortex. 1991 Jul-Aug;1(4):273-92. PMID: 1668366 below and Brain, Vol. 122, No. 5, 994-995, May 1999 below

Stress increases dopamine for concentration ONLY, joy-related dopamine is not increased Psychopharmacology of Sex

neurotransmitter

Stage One: Stage Two: Stage Three: Desire Arousal Orgasm DA + NO 5HT - melanocortin + NE NE + testosterone + melanocortin + DA +/- estrogen + testosterone + NO +/- prolactin - estrogen + 5HT ACh + DA + 5HT - “CONCLUSIONS: The common mechanism by which folic acid, H4B (tetra- hydrobiopterin), vitamin C, omega-3 fatty acids, and L -arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production.” Nutrition 2003;19: 686– 692. below Neurotransmitters and Orgasm

orgasm 5HT ejaculation and orgasm

NE Some Key HSDD Symptoms Hypothetically Linked to Specific

interests Brain Regions apathy pleasure libido physical fatigue fatigue euphoria reward motivation sexual arousal drug abuse PFC S T mental fatigue NA apathy BF Hy A NT depressed mood H delayed orgasm/anorgasmia estrogen/testosterone disturbances ejaculatory disturbances appetite/weight SC vasomotor symptoms HSDD: Low Sexual Desire, Low Dopamine nucleus accumbens (NA) “I have a headache”

MPOA DA neuron overactivation normal raphe baseline GABA hypoactivation 5HT2A 5HT1A 5HT2C neuron

5HT VTA ZI neuron

5HT2A 5HT2C Treatment of HSDD: Raising Dopamine Improves Sexual Desire nucleus accumbens (NA) “I have a headache”

MPOA overactivation normal baseline raphe hypoactivation 5HT2A 5HT1A 5HT2C

VTA ZI flibanserin

5HT2A 5HT2C Eating, Hunger and Reward Circuits nucleus accumbens (NA)

DA

DA

MPOA

VTA “The images showed that the former anorexia patients had increased activity in brain areas that make dopamine.”

Obesity was linked to decreased activity in the brains' dopamine reward centers, write Kaye and colleagues.” Hiti, M. Brain Differences in Women With The image at right (above) shows Anorexia? WebMD Medical News, July 08, 2005 dopamine metabolism in vivo in a Original article: (Below) normal human subject. http://bic.berkeley.edu/jagustlab/tools.php Mesolimbic Pathway –Untreated Schizophrenia

HIGH

positive symptoms

overactivation = pure D2 antagonist normal baseline hypoactivation Mesolimbic Pathway - D2 Antagonist

HIGHLOW

reducedpositive symptomspositive symptoms overactivation = pure D2 antagonist normal baseline hypoactivation Mesocortical Pathway to DLPFC – D2 Antagonist

LOW

production of no improvement or secondary worsening of negative cognitive symptoms symptoms

Mesocortical Pathway to VMPFC – D2 Antagonist

LOW

production of no improvement or secondary worsening of negative affective symptoms symptoms Nigrostriatal Pathway –Untreated Schizophrenia

NORMAL

overactivation = pure D2 antagonist normal baseline hypoactivation Nigrostriatal Pathway - D2 Antagonist

NORMALLOW

overactivation = pure D2 antagonist normal EPS baseline hypoactivation blockade of D2 receptors in the nigrostriatalthis upregulation dopamine may pathway lead to causes tardivethem to dyskinesia upregulate

tardive dyskinesia Tuberoinfundibular Pathway – Untreated Schizophrenia NORMAL

overactivation = pure D2 antagonist normal baseline hypoactivation Tuberoinfundibular Pathway - D2 Antagonist NORMALLOW

prolactin levels rise overactivation = pure D2 antagonist normal baseline hypoactivation Integrated Dopamine Hypothesis of Schizophreniapamine Output - After Pure D2 Antagonist Mesolimbic Mesocortical Mesocortical Nigrostriatal Tubero- Pathway Pathway Pathway Pathway infundibular to DLPFC to VMPFC Pathway

HIGHLOW LOW LOW NORMALLOW NORMALLOW

positive cognitive affective elevated symptoms symptoms symptoms prolactin parkinsonism

lack of pleasure or reward negative negative symptoms symptoms 5HT-DA Interactions

brake

substantia nigra striatum brake

raphe nucleus “people with PD (Parkinson’s Disease) have inexplicably lost more than 80 percent of dopamine-producing cells in the substantia nigra” http://www.sfn.org/index.cfm?page name=brainbriefings_parkinsonsand dopamine below “A study by researchers in Italy has found that men are twice as likely to develop symptoms of Parkinson's compared with women.” “One theory is that estrogen protects women from the disease.” “Previous studies have shown that Parkinson's appears to be less common in countries closer to the equator” http://news.bbc.co.uk/2/hi/health/1021487.stm below “A higher prevalence and incidence of Parkinson disease (PD) is observed in men and beneficial motor effects of estrogens are observed in parkinsonian women.” “Estrogens, but not androgens, are active neuroprotectants as well as progesterone and dehydroepiandrosterone.” Mol Cell Endocrinol. 2008 Aug 13;290(1-2):60-9. Epub 2008 Apr 22. PMID: 18515001 “The data obtained indicate that the potential of homocysteine to be toxic to the dopaminergic system. Consequently, long-term levodopa therapy for PD may accelerate the progression of PD, at least in part by elevated homocysteine.” Neurotoxicology. 2005 Jun;26(3):361-71. PMID: 15935208 below “Do you think that SSRI’s may have contributed to this “Some of the Parkinson’s? selective serotonin reuptake inhibitors (SSRI)-induced motor side effects are mediated by stimulating 5-HT2 receptors in the basal ganglia, probably because serotonin inhibits the subsequent neuronal dopamine release.” Avila A - J Clin Psychopharmacol - 01- OCT-2003; 23(5): 509-13 below “Impaired olfaction can predate clinical PD Brain extension in men by at least 4 years and may be a useful screening tool to detect those at high risk for development of PD in later life.” Ann Neurol. 2008 Feb;63(2):167-73. PMID: 18067173 conventional antipsychotic: serotonin-dopamine antagonist: 90% of striatal D2 receptor occupied 70-80% of striatal D2 receptor occupied Mesocortical Pathway

primary dopamine deficiency

DA cortical dopamine release enhanced by 5HT2A receptor antagonist D1 5HT2A 5HT

secondary dopamine deficiency SDA

affective cognitive negative symptoms symptoms symptoms 5HT2A and 5HT1A Receptors: Opposite Actions at Pyramidal Neurons on Glutamate Release

stimulation GLU of glutamate 5HT neuron release neurons

5HT1AR glutamate brake 5HT2AR glutamate accelerator raphe 5HT2A and 5HT1A Receptors: Opposite Actions at Pyramidal Neurons on Glutamate Release

GLU 5HT neuron inhibition neurons of glutamate release

5HT1AR glutamate brake 5HT2AR glutamate accelerator raphe Possible Reduction of Positive Symptoms by 5HT2A Antagonist

5HT2A

5HT neuron glu neuron

DA neuron VTA raphe

overactivation positive normal baseline symptoms hypoactivation Possible Reduction of Positive Symptoms by 5HT2A Antagonist 5HT2A antagonist

reduces glutamate release overactivation positive normal which reduces mesolimbic DA release baseline symptoms hypoactivation Dopamine Output - Untreated Schizophrenia Dopamine Output - After SDA Mesolimbic Mesocortical Mesocortical Nigrostriatal Tubero- Pathway Pathway Pathway Pathway infundibular to DLPFC to VMPFC Pathway

HIGHLOW NORMALLOW NORMALLOW NORMAL NORMAL

positive cognitive affective elevated symptoms symptoms symptoms prolactin parkinsonism

lack of pleasure or reward negative negative symptoms symptoms Hit-and-Run Theory Dopamine Output - Untreated Schizophrenia

Mesolimbic Mesocortical Mesocortical Nigrostriatal Tubero- Pathway Pathway Pathway Pathway infundibular to DLPFC to VMPFC Pathway

HIGHLOW NORMALLOW NORMALLOW NORMAL NORMAL

positive cognitive affective elevated symptoms symptoms symptoms prolactin parkinsonism

lack of pleasure or reward negative negative symptoms symptoms What Makes an Antipsychotic Atypical? D2 Partial Agonist Actions (DPA)

D2 PA conventional antipsychotic antagonist: deficiency of agonist

too cold antipsychotic EPS dopamine partial agonist dopamine stabilizer: balance between agonist and antagonist actions

just right

antipsychotic without EPS receptor output D2 receptor

DA

D2 antagonist

DPA Mesolimbic Dopamine Neurons

D2 receptor receptor output

DA psychosis treat with conventional treat with antipsychotic DPA

antispychotic antispychotic Nigrostriatal Dopamine Neurons

D2 receptor receptor output

DA no EPS treat with conventional treat with antipsychotic DPA

EPS no EPS DPA full agonist antagonist Dopamine Output - Untreated Schizophrenia Dopamine Output: DPA Mesolimbic Mesocortical Mesocortical Nigrostriatal Tubero- Pathway Pathway Pathway Pathway infundibular to DLPFC to VMPFC Pathway

NORMALHIGH NORMALLOW NORMALLOW NORMAL NORMAL

positive cognitive affective elevated symptoms symptoms symptoms prolactin parkinsonism

negative negative symptoms symptoms “Encouraging evidence exists for the use of omega-3 fatty acids, SAMe, folic acid and l-tryptophan adjuvantly with antidepressants to enhance response and improve efficacy.” J Psychiatr Res. 2009 Jul 16. PMID: 19616220 below Dopamine Support Precursor loading Tyrosine Stimulation of TH Iron, Folic Acid, O2, BH4 (tyrosine hydroxylase) Inhibit dopamine NOS inducers (Arginine,, reuptake Pycnogenol) Vinpocetine Stimulate dopamine Theanine release Support post synaptic DHA receptor Inhibit degradation Natural MAO Inhibitors (MAO inhibitors) (St. Johns Wort extract) Green Tea - protects dopamine neurons, + decreases acetylcholinesterase Nutritional Support

• Mucuna Puriens – L-dopa. Dopamine precursor • Beta Phenylethylamine (PEA) – Modulates the nigrostriatal pathway and stimulates dopamine release. – Influences Beta endorphins. Eat more chocolate. • Blueberry extract – Antioxidants for dopamine producing neurons. • D, L – Phenylalanine – Amino acid precursor for dopamine. Both the D and the L versions together helps with pain modulation, depression and dopamine modulation. • N-acetyl-tyrosine – Amino acid that is a precursor for dopamine. • Pyridoxal – 5 – Phosphate – Critical in dopamine creation. • Glutathione cofactors – Prevents cellular oxidative stress. Acetylcholine is Produced

glucose CAT

choline AcCoA ACh

ACh (acetylcholine) Acetylcholine Action is Terminated

glial cell

inactive BuChE

VAChT AChE choline transporter

ACh

AChE

choline Acetylcholine Projections

Higher functions Decision Making

Amygdala Arousal Controls Autonomic Responses Associated with Fear Emotional Responses Hormonal Secretions Signs of Acetylcholine problems

• Low level associations. – Memory lapses – Calculation difficulties – Decreased arousal – Impaired creativity – Diminished comprehension – Impaired judgement • Symptoms of low levels. – Loss of visual memory – Loss of verbal memory – Memory lapses – Impaired creativity – Difficulty recognizing objects and faces. – Excessive urination – Slowness of mental response Conditions

• Dementia • Alzheimer’s • Myasthenia Gravis

Acetylcholine Biosynthesis http://www.uic.edu/classes/phar/phar402/Cholinergic%20Nervous%20System%20Functions2.htm

Lipoic Acid, Healthy Insulin Estrogen (Bio Identical) “Although choline is not by strict definition a vitamin, it is an essential nutrient. Despite the fact that humans can synthesize it in small amounts, choline must be consumed in the diet to maintain health (1).” http://lpi.oregonstate.edu/infocenter/othernuts/choline/ below

“Milk, eggs, liver, and peanuts are especially rich in choline.” Acetylcholine Support

Vitamin E 12 IU (as d-alpha tocopherol)

Folate 400 mcg (as L-5-methyl tetrahydrofolate†)

Huperzine A 100 mcg (from Huperzia serrata)

tocotrienol/tocopherol (40 mg) Full Spectrum Palm Fruit Extract†† 210 mg

N-Acetyl L-Carnitine and Alpha GPC (L- alpha phosphorylcholine).

Huperzine – Multiple Mechanisms “the neuroprotective effects of huperzine A beyond its acetylcholinesterase inhibition. These effects include regulating beta- amyloid precursor protein metabolism, protecting against beta-amyloid- mediated oxidative stress and apoptosis.” Cell Mol Neurobiol. 2008 Feb;28(2):173-83. Epub 2007 Jul 27. PMID: 17657601 below “Aβ (amyloid beta) has been found in mitochondria in postmortem AD brain” Proc Natl Acad Sci U S A. 2008 September 2; 105(35): 13145–13150. doi: 10.1073/pnas.0806192105. PMCID: PMC2527349 Let’s get some green tea “Epigallocatechin-3- gallate or curcumin significantly attenuated beta amyloid - induced radical oxygen species production and beta- sheet structure formation.” Neuroreport. 2008 Aug 27;19(13):1329-33. PMID: 18695518 Beta Secretase inhibitors Green Tea and Curcumin Microglia (immune cells)

“ (DHA) decreased Abeta amyloid beta- peptide (Abeta) levels” “DHA diet also decreased the number of activated microglia in hippocampus” Neurobiol Dis. 2006 Sep;23(3):563- 72 PMID: 16765602 below “neuro-protective action of the ß- amino acid taurine against the neurotoxicity of Aß.” (Amyloid Beta) (The FASEB Journal. 2004;18:511-518.) PMID: 15003996 below Proline-Rich Polypeptide Complex Formula “Orally administered CLN showed significant stabilizing effect on cognitive functions in improving the conditions of patients suffering from mild and moderate AD (Alzheimer's disease).” The Journal of Nutrition, Health & Aging Volume , Number , 2009 1-7 below Proline-Rich Polypeptide Formula

Mild to Moderate

Alzheimer’s Progression Chart http://www2f.biglobe.ne.jp/~boke/improvingad.htm below Amyloid Plague – 21 days of PRP no treatment Treatment Allosteric Modulation of Nicotinic Receptors

Ca++ Don’t forget

• Don’t forget the entire inflammatory protocol, the energy linked excitotoxicity protocol and BBB protocol that we put together in the first module. That applies to all of the conditions we talked about this weekend, especially acetlycholine. Allosteric Modulation of Nicotinic Receptors

ACh Allosteric Modulation of Nicotinic Receptors

allosteric modulator Donepezil Donepezil Actions: CNS

central ACh neuron glial cell

AChE BuChE

AChE Donepezil Actions: CNS

central ACh neuron glial cell

AChE BuChE

donepezil

AChE Rivastigmine Rivastigmine Actions: CNS

central ACh neuron glial cell

AChE BuChE

AChE Rivastigmine Actions: CNS

glial cell

BuChE

rivastigmine AChE Rivastigmine Actions: Gliosis

glial cell glial cell

BuChE BuChE

rivastigmine glial cell glial cell AChE

BuChE BuChE Rivastigmine Actions: Peripheral

peripheral ACh neuron

AChE

ACh BuChE AChE

BuChE AChE Rivastigmine Actions: Peripheral

peripheral ACh neuron

AChE

rivastigmine

BuChE AChE

BuChE AChE Rivastigmine Actions: Peripheral

peripheral ACh neuron

AChE

rivastigmine

BuChE AChE

BuChE AChE Galantamine Galantamine Actions

glial cell AChE BuChE

Ca++

AChE Galantamine Actions

glial cell

BuChE

Ca++

galantamine AChE Galantamine Actions: Nicotinic Allosteric Modulation

glial cell

BuChE

Ca++

galantamine AChE Galantamine Actions: Nicotinic Allosteric Modulation

glial cell

BuChE

Ca++

galantamine AChE normal neurotransmissionresting state

glycine Ca++ glu Mg++ NMDA-R

depolarization normal neurotransmission

depolarization

depolarization

LTP

learning neuroplasticity memory Alzheimernormal neurotransmissionexcitotoxicity

depolarization

memory problems free radical memantineAlzheimer and new resting stateexcitotoxicity in Alzheimer’s disease

memantine

memory problems

free radical memantine and new resting state in Alzheimer’s disease

depolarization

LTP

learning neuroplasticity memory